title: Inhibition of collagen-induced discoidin domain receptor 1 and 2 activation by imatinib, nilotinib and dasatinib.
abstract: Imatinib, nilotinib and dasatinib are protein kinase inhibitors which target the tyrosine kinase activity of the Breakpoint Cluster Region-Abelson kinase (BCR-ABL) and are used to treat chronic myelogenous leukemia. Recently, using a chemical proteomics approach another tyrosine kinase, the collagen receptor Discoidin Domain Receptor1 (DDR1) has also been identified as a potential target of these compounds. To further investigate the interaction of imatinib, nilotinib and dasatinib with DDR1 kinase we cloned and expressed human DDR1 and developed biochemical and cellular functional assays to assess their activity against DDR1 and the related receptor tyrosine kinase Discoidin Domain Receptor2 (DDR2). Our studies demonstrate that all 3 compounds are potent inhibitors of the kinase activity of both DDR1 and DDR2. In order to investigate the question of selectivity among DDR1, DDR2 and other tyrosine kinases we have aligned DDR1 and DDR2 protein sequences to other closely related members of the receptor tyrosine kinase family such as Muscle Specific Kinase (MUSK), insulin receptor (INSR), Abelson kinase (c-ABL), and the stem cell factor receptor (c-KIT) and have built homology models for the DDR1 and DDR2 kinase domains. In spite of high similarity among these kinases we show that there are differences within the ATP-phosphate binding loop (P-loop), which could be exploited to obtain kinase selective compounds. Furthermore, the potent DDR1 and DDR2 inhibitory activity of imatinib, nilotinib and dasatinib may have therapeutic implications in a number of inflammatory, fibrotic and neoplastic diseases.
authors.affiliation: Novartis Institutes of Biomedical Research, Respiratory Disease Area, Wimblehurst Road, Horsham, RH12 5AB, UK.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Day
authors.forename: Beatrice
authors.initials: B
authors.lastname: Waters
authors.forename: Katrin
authors.initials: K
authors.lastname: Spiegel
authors.forename: Tanja
authors.initials: T
authors.lastname: Alnadaf
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Buchdunger
authors.forename: Christoph
authors.initials: C
authors.lastname: Walker
authors.forename: Gabor
authors.initials: G
authors.lastname: Jarai
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D001549:Benzamides; D002460:Cell Line; D003001:Cloning, Molecular; D003094:Collagen / Q000378:metabolism; D000069439:Dasatinib; D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000503:physiopathology; D008958:Models, Molecular; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D020794:Receptor Protein-Tyrosine Kinases / Q000187:drug effects* / Q000378:metabolism; D011975:Receptors, Mitogen / Q000187:drug effects* / Q000378:metabolism; D040681:Structural Homology, Protein; D013844:Thiazoles / Q000494:pharmacology
chemical_list: D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011975:Receptors, Mitogen; D013844:Thiazoles; D000068877:Imatinib Mesylate; D000255:Adenosine Triphosphate; D003094:Collagen; C092030:DDR1 protein, human; D000070819:Discoidin Domain Receptor 1; D000070818:Discoidin Domain Receptors; D020794:Receptor Protein-Tyrosine Kinases; C498826:nilotinib; D000069439:Dasatinib